The Search Continues for Viable Biomarkers in Hepatocellular Carcinoma

Targeted Therapies in OncologyJanuary I, 2024
Volume 13
Issue 1
Pages: 16

Research is ongoing to identify biomarkers in hepatocellular carcinoma that are predictive in nature, according to Richard Kim, MD.

Richard Kim, MD

Richard Kim, MD

Service Chief Medical Gastrointestinal Oncology

Moffitt Cancer Center

Professor of Oncology

University of South Florida Morsani College of Medicine

Tampa, FL

The search for biomarkers in hepatocellular carcinoma continues despite recent approvals for immune checkpoint inhibitor combinations, tyrosine kinase inhibitors [TKIs], and antiangiogenesic agents. Biomarkers can be either predictive or prognostic and the only biomarker that has been used clinically is the prognostic biomarker α-fetoprotein (AFP).1

“AFP is the only biomarker that we draw on a regular basis. Everything else is an exploratory analysis,” Richard Kim, MD, professor of oncology, University of South Florida Morsani College of Medicine and service chief, medical gastrointestinal oncology, Moffitt Cancer Center, both in Tampa, Florida, said during an interview with Targeted Therapies in Oncology.

AFP has limitations, though, and these include expression in other cancers and diseases, such as chronic hepatitis, liver cirrhosis, and neurodegenerative diseases.2 Further, AFP has a relatively inadequate sensitivity and specificity for surveillance, poor positive predictive value, and inadequate diagnostic accuracy for early-stage hepatocellular carcinoma (HCC).3 Despite these challenges, AFP remains a widely used biomarker because of its low cost, ease of measurement, and widespread availability.

AFP-L3, a lens culinaris agglutinin-reactive fraction of AFP, has been shown to have greater specificity and a better diagnostic characteristic than AFP.4

Although AFP-L3 has greater specificity than AFP, its sensitivity remains suspect, but the FDA has approved AFP-L3 for the assessment of liver cancer risk as part of the GALAD (gender, age, AFP-L3, AFP, des-γ-carboxy prothrombin [DCP]) score.5 This score combines 3 biomarkers with the patient’s age and gender to estimate the probability of HCC in patients with chronic liver disease.

Another potential serum biomarker is DCP, which has been found to be elevated in patients with HCC. Studies suggest that DCP levels may correlate with HCC stage and survival, with sensitivity that rivals AFP in detection of HCC.6,7

A study by Carlo Saitta, MD, and colleagues reported that DCP was a useful tool for defining liver nodules in 90 patients with liver cirrhosis, providing high diagnostic accuracy for HCC when used in combination with AFP.8 At a cutoff of 60 mAU/mL, DCP was significantly associated with HCC in both univariate and multivariate analysis (P = .016 and P = .032, respectively). AFP at a cutoff of 6.5 ng/mL was not associated with HCC at univariate analysis (P = .246), the investigators reported.8

In the study, DCP was found to have a sensitivity of 60%, specificity of 80%, positive predictive value of 80%, and negative predictive value of 73%, compared with 67%, 68%, 63% and 72%, respectively, for AFP.8

Predictive Biomarkers

Research is ongoing to identify biomarkers that are predictive in nature, said Kim. Identifying the biomarker that will predict whether a patient will respond to therapy is highly sought out.

“In advanced HCC, there are 2 broad approaches that we use: immunotherapy-based regimens or targeted-based regimens, specifically tyrosine kinase inhibitors [TKIs],” Kim said.

“Currently, standard therapy in advanced HCC is immunotherapy. But we don’t have a reliable biomarker at this time,” Kim continued. “With response rates of 25% to 30%,” Kim said, “having a biomarker that we could select at the beginning of therapy to figure out who would benefit from it remains an ongoing goal.”

PD-1/PD-L1 Pathway

A key pathway undergoing exploration in HCC is the PD-1/PD-L1 pathway.

In 2017, the phase 1/2 CheckMate040 trial (NCT01658878)9 showed that nivolumab (Opdivo) was effective in the second-line setting resulting in an FDA accelerated approval.10

Unfortunately, nivolumab is no longer available as a single agent since its accelerated approval was overturned based on the results of the CheckMate-459 study (NCT02576509).

Second-line pembrolizumab (Keytruda) has also demonstrated promise, according to findings from the phase 3 KEYNOTE-240 trial (NCT02702401).11 Eligible patients (n = 413) with advanced HCC and previously treated with sorafenib (Nexavar) were randomly assigned 2:1 to receive pembrolizumab and best supportive care or placebo and best supportive care.

Median overall survival (OS) was 13.9 months (95% CI, 11.6-16.0) for pembrolizumab vs 10.6 months (95% CI, 8.3-13.5) for placebo (HR, 0.781; 95% CI, 0.611-0.998; P = .0238).

Median progression-free survival (PFS) for pembrolizumab was 3.0 months (95% CI, 2.8-4.1) vs 2.8 months (95% CI, 2.5-4.1) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609-0.987; P = .0186) and 3.0 months (95% CI, 2.8-4.1) vs 2.8 months (95% CI, 1.6-3.0) at final analysis (HR, 0.718; 95% CI, 0.570-0.904; P = .0022).11

A phase 1 study (NCT02407990) evaluating tislelizumab, an IgG4 monoclonal antibody, suggests the agent is well tolerated with one study evaluating it in patients with esophageal, gastric, hepatocellular, and non–small cell lung cancer (NSCLC).12

Eligible patients were treated with tislelizumab at 2 mg/kg or 5 mg/kg every 2 weeks or 3 weeks.

Overall, 97% received 5 mg/kg every 3 weeks. Adverse events (AEs) were assessed per National Cancer Institute Common Terminology Criteria for Adverse Events 4.03 criteria and tumor assessments performed every 9 weeks using RECIST v1.1.

Treatment-related AEs (TRAEs) occurring in 5% or more of patients were fatigue (8.7%), decreased appetite (6.8%), rash (6.8%), and hypothyroidism (6.3%). Grade 3 or greater TRAEs occurring in 2 or more patients were pneumonitis (n = 3), elevated aspartate aminotransferase level (n = 3), and elevated alanine aminotransferase level (n = 2).

Grade 5 TRAEs were reported in 2 patients: pneumonitis in a patient with NSCLC with compromised pulmonary function, and acute hepatitis in a patient with HCC with rapidly progressing disease. Median duration of study follow-up ranged from 4.9 to 9.9 months.

Another IgG4 monoclonal antibody, sintilimab, in combination with the anti-VEGF monoclonal antibody, IBI305, also showed promising efficacy and a favorable safety profile in a phase 1b study (NCT04072679) in patients who received either a low-dose or high-dose of sintilimab. The objective response rate per RECIST v1.1 was 24.1% (95% CI, 10.3%-43.5%) in the low-dose group, and 33.3% (95% CI,13.3%-59.0%) in the high-dose group.

As with the cutoff date, the median PFS had not been reached and the 6-month PFS rates were 60.5% (95%CI 36.1%-78.0%) and 75.8% (95% CI, 47.3%-90.2%), respectively.13

Combination Therapy

The combination therapy of atezolizumab (Tecentriq) and bevacizumab (Avastin) was also evaluated in patients with unresectable HCC in the efficacy and safety IMbrave150 study (NCT03434379).14

The trial investigated the efficacy and safety of combining atezolizumab and bevacizumab in the treatment of advanced HCC against sorafenib.

The primary end point of the study was OS, and the trial demonstrated that the combination of atezolizumab and bevacizumab significantly improved OS (19.2 months vs 13.4 months, respectively) and PFS (6.9 months vs 4.3 months) compared with sorafenib.

The trial led to the approval of atezolizumab in combination with bevacizumab as a first-line treatment for unresectable or metastatic HCC.14

Another combination trial, the open label, phase 3 HIMALAYA trial (NCT03298451) evaluated tremelimumab (Imjudo) and durvalumab (Imfinzi) in the first-line setting in patients with unresectable HCC.15

In the trial, 1171 patients were randomized to receive either the STRIDE regimen (a single dose of tremelimumab with regular intervals of durvalumab), durvalumab alone, or sorafenib alone. The primary objective was OS for STRIDE vs sorafenib and the secondary objective was OS noninferiority of durvalumab to sorafenib.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8% (STRIDE), 12.9% (durvalumab), and 36.9% (sorafenib) of patients. Grade 3/4 hepatic TRAEs occurred in 5.9% (STRIDE), 5.2% (durvalumab), and 4.5% (sorafenib) of patients.

Researchers determined that durvalumab was noninferior to sorafenib with favorable safety.

The combination of a single priming dose of tremelimumab and durvalumab in STRIDE displayed superior efficacy and a favorable risk-benefit profile vs sorafenib and now is approved for first-line advanced HCC.15


Turning to TKIs, sorafenib was evaluated in the phase 3 SHARP trial (NCT00105443) that encompassed 602 patients with advanced HCC who had not received systemic treatment.16 Patients were randomly assigned to receive either sorafenib (400 mg twice daily) or placebo. Median OS was 10.7 months for the sorafenib group and 7.9 months for the placebo group (HR, 0.69; 95% CI, 0.55-0.87; P < .001). There was no significant difference between the 2 groups in the median time to symptomatic progression (4.1 months vs 4.9 months, respectively, P = .77).16

Ten plasma biomarkers were reviewed in SHARP: angiopoietin-2 (Ang-2 ), EGF, basic fibroblast growth factor (FGF), VEGF, sVEGFR-2, sVEGFR-3, hepatocyte growth factor, stem cell factor and its soluble receptor KIT , insulinlike growth factor 1, and circulating RAS. Of these, Ang-2 and VEGF levels showed value as prognostic biomarkers.17

In the phase 3 REFLECT trial (NCT01761266), lenvatinib (Lenvima) was shown to be noninferior to sorafenib in OS with no new safety signals for lenvatinib. In this study, VEGF, Ang-2, FGF19, FGF21, and FGF23 were analyzed.18

The trial’s primary end point was OS and secondary end points were efficacy and other safety end points. Investigators reported an OS of 13.6 months in the treatment arm (95% CI, 12.1-14.9) vs 12.3 months with sorafenib (95% CI, 10.4-13.9), demonstrating noninferiority of lenvatinib to sorafenib (HR, 0.92; 95% CI, 0.79-1.06).

The phase 3 RESORCE trial (NCT01774344) showed that regorafenib (Stivarga) provided a survival benefit in patients with HCC who progressed from sorafenib. Biomarkers analyzed in this trial included Ang-1, cystatin-B, the latency-associated peptide TGF-β1, LOX1, and MIP-1α.19

Eligible patients were adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh class A liver function.

Participants were randomly assigned (2:1) by a computer-generated randomization list and interactive voice response system and stratified by geographical region, ECOG performance status, macrovascular invasion, extrahepatic disease, and AFP level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1 through 3 of each 4-week cycle. The primary end point was OS (defined as time from randomization to death due to any cause) and analyzed by intention to treat.

In the trial, regorafenib improved median OS vs placebo (n = 194) in patients with HCC who had progressed on sorafenib (HR, 0.63; 95% CI, 0.50-0.79; P < .0001). The median OS with regorafenib was 10.6 months (95% CI, 9.1-12.1) vs 7.8 months (95% CI, 6.38.8) with placebo.

Looking Ahead

A variety of novel biomarkers for HCC have been proposed, but many biomarkers in early-stage HCC have been evaluated in early-phase studies. In more advanced disease, prognostic and predictive biomarkers are evaluated in exploratory studies of randomized clinical trials.

To move the field ahead, Kim sees 2 possibilities. “First, we need to find a better biomarker to determine the who will benefit from immunotherapies compared to TKIs,” Kim said. “And second, once progression on immunotherapy occurs, what is our next step in therapy? Immunotherapy has been a standard for at least 2 years, so how do we sequence from first line to second line? It remains an unmet need,” Kim said.

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  8. Saitta C, Raffa G, Alibrandi A, et al. PIVKA-II is a useful tool for diagnostic characterization of ultrasound-detected liver nodules in cirrhotic patients. Medicine (Baltimore). 2017;96(26):e7266. doi:10.1097/MD.0000000000007266
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